Activated blood leukocytes elaborate a low molecular weight, heat labile protein that is responsible for the fever seen in infectious disease. One way that leukocytes are activated is coming into contact with endotoxin or bacterial lipopolysaccharide. The objective of the proposed work is to understand how endotoxin tells the leukocyte to make pyrogen. The finding that endotoxin can promote formation of pyrogen in cell-free extracts of leukocytes suggests that it works below the translational level of protein synthesis. Our current thinking is that endotoxin directs the folding of a leukocyte protein by interfering with pairing of protein sulfhydryl groups. We propose to study: 1) the effect of endotoxin injection into rabbits on the level of disulfide- containing enzymes in leukocytes and other tissues, and 2) the effect of endotoxin on pairing of half-cystine residues of reduced ribonuclease undergoing air oxidation. Preliminary experiments indicate that endotoxin affects the process described in (2). The presence of various proteins and lipids in mixtures on the process will be investigated.